Programmed cell-death (also known as apoptosis) is a form of cell-death defined by morphological and biochemical characteristics. Apoptosis is a characteristic of the normal developmental process as well as a response of cells to stress or other environmental insults. Apoptosis is characterized by membrane blebbing and retention of its integrity, cellular and cytoplasmic shrinkage, chromosome fragmentation and condensation, and endonuclease activation resulting in the characteristic 180 bp DNA ladder. During this process, the nuclear lamins are cleaved inducing their disassembly. Apoptosis does not induce an inflammatory response because cells form apoptotic bodies which are phagocytozed by neighboring cells. A number of stresses can induce apoptosis in vitro and in vivo. The administration of glucocorticoids, reduction of hormone and/or growth factor levels, chemotherapy (toxic agents), mechanical injury and DNA damage can all result in apoptosis. Apoptosis is also induced by aberrant cell cycle activity, and it can be triggered in cells that express the Fas receptor with crosslinking antibodies or the natural Fas ligand. High frequencies of apoptotic cell-death are associated in a diverse array of pathological disorders.
Akt (c-Akt) is a proto-oncogene encoding a serine-threonine kinase (Testa, J. R. and Bellacosa, A., Leukemia Res., 1997, 21:1027-1031). It is the cellular homolog of the viral oncoprotein v-Akt, and is related to protein kinase-C (PKC) within the catalytic domain. However, c-Akt differs from the PKC family members by the presence of a pleckstrin homology (PH) domain at its N-terminus that is involved in the regulation of the activity of the enzyme by growth factors and intracellular signaling molecules. Various extracellular stimuli reportedly activate Akt through the phosphoinositide 3-kinase (PI 3-kinase) pathway (Datta, K. et al., J. Biol. Chem., 1996, 271:30835-30839; Franke, T. F., et al., Cell, 1995, 81:727-736; King, W. G. et al., Mol. Cell. Biol., 1997, 17:4406-4418). The lipid products of the PI 3-kinase reaction may activate Akt either by binding to the Akt pleckstrin homology domain (Franke, T. F. et al., 1997, Cell, 88:435:437), or by activating a protein kinase that phosphorylates Akt (Kohn, A. D., et al., J. Biol. Chem., 1996, 271:21920-21926; Stokoe et al., Science, 1997, 277:567-570). Activation of Akt reportedly inhibits apoptosis induced by growth factor withdrawal or irradiation in neural cells, fibroblasts, and lymphocytes (Franke, T. F., et al., Science, 1997, 275:665-668; Hemmings, Science, 1997, 275:628-630). Recently, it has been reported that Akt phosphorylates the pro-apoptotic protein Bad leading to Bad inactivation and cell survival (Datta, K., et al., Cell, 1997, 91:231-241; Peso, L., et al., Science, 1997, 278:687-689).